GSK-3 protein and the heart: friend or foe?

Metabolic syndrome manifesting as obesity, insulin resistance and type 2 diabetes mellitus is currently pandemic. Each of these, in its own right, is strongly related to the development of cardiovascular disease. The cardiomyopathy associated with these disorders is characterised by curtailed glucose uptake and utilisation, elevated risk of damage after ischaemia and contractile dysfunction. Current research have indicated that the serine/threonine kinase, glycogen synthase kinase 3 (GSK-3), may play a central role in the development of all these dysfunctions. The development of new generations of inhibitors of this kinase, has renewed interest in its utilisation as therapeutic target. This review has therefore focused on the role of GSK-3 in the development of the obesity-related cardiomyopathy and has highlighted and discussed the detrimental as well as beneficial effects of the GSK-3 inhibitors that are currently available. We have discussed the different roleplayers such as the insulin signalling pathway, modulation of apoptosis and mitochondrial function, SERCA2 expression and regulation of the development of hypertrophy in the context of GSK-3 activity

Cardioprotective and anti-hypertensive effects of Prosopis glandulosa in rat models of pre-diabetes

AIM: Obesity and type 2 diabetes present with two debilitating complications, namely, hypertension and heart disease. The dried and ground pods of Prosopis glandulosa (commonly known as the Honey mesquite tree) which is part of the Fabaceae (or legume) family are currently marketed in South Africa as a food supplement with blood glucose-stabilising and anti-hypertensive properties. We previously determined its hypoglycaemic effects, and in the current study we determined the efficacy of P glandulosa as anti-hypertensive agent and its myocardial protective ability. METHODS: Male Wistar rats were rendered either pre-diabetic (diet-induced obesity: DIO) or hypertensive (high-fat diet: HFD). DIO animals were treated with P glandulosa (100 mg/kg/day for the last eight weeks of a 16-week period) and compared to age-matched controls. Hearts were perfused ex vivo to determine infarct size. Biometric parameters were determined at the time of sacrifice. Cardiac-specific insulin receptor knock-out (CIRKO) mice were similarly treated with P glandulosa and infarct size was determined. HFD animals were treated with P glandulosa from the onset of the diet or from weeks 12–16, using captopril (50 mg/kg/day) as the positive control. Blood pressure was monitored weekly. RESULTS: DIO rats and CIRKO mice: P glandulosa ingestion significantly reduced infarct size after ischaemia–reperfusion. Proteins of the PI-3-kinase/PKB/Akt survival pathway were affected in a manner supporting cardioprotection. HFD model: P glandulosa treatment both prevented and corrected the development of hypertension, which was also reflected in alleviation of water retention. CONCLUSION: P glandulosa was cardioprotective and infarct sparing as well as anti-hypertensive without affecting the body weight or the intra-peritoneal fat depots of the animals. Changes in the PI-3-kinase/PKB/Akt pathway may be causal to protection. Results indicated water retention, possibly coupled to vasoconstriction in the HFD animals, while ingestion of P glandulosa alleviated both. We concluded that treatment of pre-diabetes, type 2 diabetes or hypertension with P glandulosa poses possible beneficial health effects.Department of HE and Training approved lis

Reviewing evidence of marine ecosystem change off South Africa

Recent changes have been observed in South African marine ecosystems. The main pressures on these ecosystems are fishing, climate change, pollution, ocean acidification and mining. The best long-term datasets are for trends in fishing pressures but there are many gaps, especially for non-commercial species. Fishing pressures have varied over time, depending on the species being caught. Little information exists for trends in other anthropogenic pressures. Field observations of environmental variables are limited in time and space. Remotely sensed satellite data have improved spatial and temporal coverage but the time-series are still too short to distinguish long-term trends from interannual and decadal variability. There are indications of recent cooling on the West and South coasts and warming on the East Coast over a period of 20 - 30 years. Oxygen concentrations on the West Coast have decreased over this period. Observed changes in offshore marine communities include southward and eastward changes in species distributions, changes in abundance of species, and probable alterations in foodweb dynamics. Causes of observed changes are difficult to attribute. Full understanding of marine ecosystem change requires ongoing and effective data collection, management and archiving, and coordination in carrying out ecosystem research.DHE

The effect of a preparation of minerals, vitamins and trace elements on the cardiac gene expression pattern in male diabetic rats

BACKGROUND: Diabetic patients have an increased risk of developing cardiovascular diseases, which are the leading cause of death in developed countries. Although multivitamin products are widely used as dietary supplements, the effects of these products have not been investigated in the diabetic heart yet. Therefore, here we investigated if a preparation of different minerals, vitamins, and trace elements (MVT) affects the cardiac gene expression pattern in experimental diabetes. METHODS: Two-day old male Wistar rats were injected with streptozotocin (i.p. 100 mg/kg) or citrate buffer to induce diabetes. From weeks 4 to 12, rats were fed with a vehicle or a MVT preparation. Fasting blood glucose measurement and oral glucose tolerance test were performed at week 12, and then total RNA was isolated from the myocardium and assayed by rat oligonucleotide microarray for 41012 oligonucleotides. RESULTS: Significantly elevated fasting blood glucose concentration and impaired glucose tolerance were markedly improved by MVT-treatment in diabetic rats at week 12. Genes with significantly altered expression due to diabetes include functional clusters related to cardiac hypertrophy (e.g. caspase recruitment domain family, member 9; cytochrome P450, family 26, subfamily B, polypeptide; FXYD domain containing ion transport regulator 3), stress response (e.g. metallothionein 1a; metallothionein 2a; interleukin-6 receptor; heme oxygenase (decycling) 1; and glutathione S-transferase, theta 3), and hormones associated with insulin resistance (e.g. resistin; FK506 binding protein 5; galanin/GMAP prepropeptide). Moreover the expression of some other genes with no definite cardiac function was also changed such as e.g. similar to apolipoprotein L2; brain expressed X-linked 1; prostaglandin b2 synthase (brain). MVT-treatment in diabetic rats showed opposite gene expression changes in the cases of 19 genes associated with diabetic cardiomyopathy. In healthy hearts, MVT-treatment resulted in cardiac gene expression changes mostly related to immune response (e.g. complement factor B; complement component 4a; interferon regulatory factor 7; hepcidin). CONCLUSIONS: MVT-treatment improved diagnostic markers of diabetes. This is the first demonstration that MVT-treatment significantly alters cardiac gene expression profile in both control and diabetic rats. Our results and further studies exploring the mechanistic role of individual genes may contribute to the prevention or diagnosis of cardiac complications in diabetes

Loss of DPP4 activity is related to a prothrombogenic status of endothelial cells: implications for the coronary microvasculature of myocardial infarction patients

Pro-coagulant and pro-inflammatory intramyocardial (micro)vasculature plays an important role in acute myocardial infarction (AMI). Currently, inhibition of serine protease dipeptidyl peptidase 4 (DPP4) receives a lot of interest as an anti-hyperglycemic therapy in type 2 diabetes patients. However, DPP4 also possesses anti-thrombotic properties and may behave as an immobilized anti-coagulant on endothelial cells. Here, we studied the expression and activity of endothelial DPP4 in human myocardial infarction in relation to a prothrombogenic endothelial phenotype. Using (immuno)histochemistry, DPP4 expression and activity were found on the endothelium of intramyocardial blood vessels in autopsied control hearts (n = 9). Within the infarction area of AMI patients (n = 73), this DPP4 expression and activity were significantly decreased, coinciding with an increase in Tissue Factor expression. In primary human umbilical vein endothelial cells (HUVECs), Western blot analysis and digital imaging fluorescence microscopy revealed that DPP4 expression was strongly decreased after metabolic inhibition, also coinciding with Tissue Factor upregulation. Interestingly, inhibition of DPP4 activity with diprotin A also enhanced the amount of Tissue Factor encountered and induced the adherence of platelets under flow conditions. Ischemia induces loss of coronary microvascular endothelial DPP4 expression and increased Tissue Factor expression in AMI as well as in vitro in HUVECs. Our data suggest that the loss of DPP4 activity affects the anti-thrombogenic nature of the endothelium

Protein kinase B in the diabetic heart

This paper summarizes data from different studies all aimed at elucidating regulation of protein kinase B in the diabetic heart. Two rat models of type 2 diabetes mellitus ((i) elicited via neonatal streptozotocin injection (Stz) and (ii) Zucker fa/fa rats), were used as well as different experimental models viz isolated, Langendorff perfused hearts as well as adult ventricular myocytes. Glucose uptake was elicited by a variety of stimuli and the activation of PKB measured in tandem. Basal glucose uptake was impaired in both diabetes models while basal phosphorylation of PKB differed, showing lower levels in the Stz model but higher levels in the Zucker rats. Neither 100 nM insulin nor 10-8 M isoproterenol could stimulate PKB phosphorylation to the same extent in the diabetic myocardium as in controls, regardless of the method used, but a combination of these stimuli resulted in an additive response. Concurrent glucose uptake however, was not additive. Wortmannin abolished both insulin and isoproterenol stimulation of glucose uptake as well as PKB phosphorylation. In contrast to the above-mentioned results, the protein tyrosine phosphatase inhibitor vanadate, alone or in combination with insulin, elicited PKB phosphorylation to the same extent in diabetic cardiomyocytes as in controls. Despite this, glucose uptake stimulated by vanadate or insulin in combination with vanadate was attenuated. The combination of insulin and vanadate may however be beneficial to the diabetic heart as it resulted in improved glucose transport. Results from the different studies can be summarized as follows: (i) dysregulation of PKB is evident in the diabetic myocardium, (ii) PKB activation is not always directly correlated with glucose uptake and (iii) insulin resistance is associated with multiple alterations in signal transduction, both above and below PKB activation.Articl

PKB in diabetic myocardiopathy.

GesondheidswetenskappeGeneeskundige FisiologiePlease help us populate SUNScholar with the post print version of this article. It can be e-mailed to: [email protected]